HCTZ and melanoma risk, and not such a great BP med

A recent case-control study of a large, comprehensive Danish database found a significant connection between patients prescribed hydrochlorothiazide (HCTZ) and the risk of malignant melanoma (see htn hctz melanoma jamaintmed2018 in dropbox, or doi:10.1001/jamainternmed.2018.1652).

Details:
-- 19,273 patients with histologically verified melanoma were compared to 192,730 population controls.
-- All were without a prior history of cancer (except non-melanoma skin cancer), organ transplant, HIV infection, or azathioprine use

Results:
-- those who ever used HCTZ: 1958 melanoma cases vs 17,244 in controls; 17% increase with HCTZ (1.11-1.23), controlling for age, sex, history of nonmelanoma skin cancer, other comorbidity (diabetes, COPD, alcohol use disorder, chronic renal failure), Charlson Comorbidity Index score, highest level of the achieved education, and use of specific drugs (topical or oral retinoids, tetracycline, macrolides, aminoquinolones, amiodarone, methoxypsoralen, low-dose aspirin, NSAIDs, statins, oral steroids)
-- there was no dose-response curve by cumulative dose of HCTZ taken:
    -- 1 to 25,000 mg: 14% increased risk controlling for the above
    -- 25,000 to 50,000 mg: 18% increased risk
    -- 50,000 to 100,000 mg: 21% increased risk
    -- >100,000 mg: 21% increased risk
-- higher odds ratios were found for nodular melanoma (OR 2.05) and lentigo melanoma (OR 1.61). Superficial spreading melanoma was not significantly associated
-- there was no statistically significant association for bendroflumethiazide, ACE inhibitors, ARBs, or calcium channel blockers (suggesting that the relationship is not with hypertension but with the actual drug used to treat it)

Commentary:
-- limitations of this study include: lacking data on sun exposure, skin pigmentation, or family history of melanoma.
-- Two other studies from Northern Denmark: 1 found a dose-response curve (overall 32% increased melanoma risk associated with HCTZ, and a 43% increased risk for HCTZ combined with amiloride); the other study did not find an association between HCTZ /amiloride and melanoma risk
-- This same group had previously found a significant relationship between HCTZ and lip cancer (see https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1307567 ), comparing 712 patients with lip cancer vs 22,904 controls: those with at least a 5 year supply of HCTZ had an odds ratio of 4.22 (i.e. more than fourfold rate of lip cancer) if on HCTZ, OR 2.82 if on HCTZ /triamterene, and 2.50 if on nifedipine, controlling for cigarette smoking. And another study finding a 29% increase in basal cell carcinomas plus a 4-fold risk of squamous cell carcinomas (see https://www.jaad.org/article/S0190-9622(17)32741-X/fulltext​ )
-- thiazides have known photosensitizing properties (as do other diuretics, including loop diuretics, spironolactone, and indapamide). Also, nifedipine is a photosensitizer, which might explain its apparent increased risk for the lip cancer.

i am using this article about melanoma (and lip cancer) really as a segue to supplement my prior blogs finding that HCTZ, the most commonly prescribed antihypertensive in the world , is not a very good antihypertensive, though >134.1 million prescriptions were written in 2008 and more than 48 million for monotherapy (see http://gmodestmedblogs.blogspot.com/2016/04/chlorthalidone-is-better-than-hctz-for.html  ). will summarize the salient points from this blog:

--there are essentially no clinical outcome data on HCTZ 12.5 mg, a very commonly used dose now. It is notable that the old JNC8 "recommends thiazide or thiazide-like diuretics", and for HCTZ, "using 12.5 to 25 mg/d as initial dose", but the new ACC/AHA guidelines state that chlorthalidone is the preferred diuretic, and HCTZ should be prescribed at least in the 25-50 mg dosages (see http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html ). the old studies finding actual clinical efficacy for thiazides were done using higher doses
--there are even some data that combinations of other antihypertensives with low dose HCTZ are inferior to combinations with calcium-channel blockers (CCBs): eg the ACCOMPLISH trial found that there was a morbidity/mortality advantage of the combination benazepril/amlodipine over benazepril/HCTZ
--there are med adherence data suggesting that HCTZ is among the worst (eg, see htn med compliance 2010 in dropbox, or Friedman O. Am J Med 2010: 123; 173)
--an article by Messerli looked at data on 24-hour ambulatory BP monitoring by several different antihypertensives, also finding that HCTZ in doses of 12.5 to 25mg had 1/2 the blood pressure reduction of ACE-I, ARBs, b-blockers, and CCBs (6.5/4.5 mmHg, vs 12/8 mmHg reductions in the other meds) though in-clinic BP recordings all have about the same BP reduction. ie, those on HCTZ had similar office blood pressures as with the other drugs, BUT the 24-hour average blood pressure was much higher with HCTZ. And one concern is that the diurnal variation of stroke incidence, for example, is in the early AM hours, when the effect of HCTZ has largely worn off (see htn HCTZ Meta-anaylsis messerli am j cardiol 2011​ in dropbox, or Messerli F. J Am Coll Cardiol 2011; 57: 590). 
--there are some additional studies finding that blood pressure variability may be a predictor of cardiovascular events (see http://gmodestmedblogs.blogspot.com/2016/09/blood-pressure-variability-increases.html  ). a recent study suggested that amlodipine was somewhat better than other meds, though chlorthalidone and losartan were just about as good (see htn bp variability amlodipine htn2017 in dropbox, or DOI: 10.1161/HYPERTENSIONAHA.117.10087, as well as bp variability amlod better JASH2014 in dropbox, or 

doi.org/10.1016/j.jash.2014.02.004)

--so, what should one do?
    ​--i do not think we should be prescribing HCTZ in the 12.5-25mg doses as a single agent for hypertension. it is much less effective than the other meds on a 24-hour basis (though we can be fooled, since daytime office blood pressure reductions are similar to the other meds), and it seems to have about the worst antihypertensive med adherence rate. And these studies on melanoma, lip cancer, and other skin cancers is yet another reason not to use HCTZ
     ​--in terms of pharmacokinetics, i think amlodipine is the best. it does well in the 24-hour ambulatory blood pressure studies, and there are other studies showing less blood pressure variability with it. there have also been several studies on blood pressure variability showing an increase in strokes in those on meds with more variability (including ACE-I). Extended-release nifedipine has been less-studied but may be as good in terms of 24hour ambulatory BP monitoring  (see https://link.springer.com/article/10.2165/00044011-199700131-00012).
    --if a person is on an ACE-I/ARB and needs a second agent, it may make sense to use a calcium channel blocker over the combo pill with HCTZ
    --if one wants to use a diuretic, several studies have suggested that chlorthalidone is better than HCTZ (and that is the preferred diuretic in the AHA/ACC guidelines). the 25-mg pill is the one available, but is associated with lots of hypokalemia. some people have had good success with breaking that pill in half or even quarters. Though it probably has about the same level of photosensitizing as HCTZ….